The overall working hypothesis that continues to guide this project is that exposure to novelty activates the mesolimbic dopamine (DA) reward pathway in a manner similar to drugs of abuse. During the previous phase of the project, we have shown that a brief period of exposure to novelty activates the mesolimbic DA system and decreases amphetamine self-administration in a random population of rats, suggesting that novelty may substitute for drug reward. Further, we have found that individual differences in response to inescapable novelty predict intravenous amphetamine self-administration, whereas individual differences in response to free-choice novelty predict amphetamine conditioned place preference. In keeping with the theme of the Center for Prevention Research, this project now will determine if individual differences in response to novelty also predict the ability of novel stimuli to alter amphetamine reward. The current proposal will also ascertain if individual differences exist in the mesolimbic DA system using both in vivo and in vitro neurochemical techiques, and will determine if novelty seeking is in part under genetic control. To the extent that both novelty and drugs of abuse activate the same mesolimbic DA system, this would suggest that novel stimulation may substitute for drug reward. The ability of novelty to alter amphetamine self-administration will be examined in a random sample of rats differing in response to novelty (high vs. low responders). If novelty is effective in reducing amphetamine self-administration, then this preclinical information would provide the impetus for examining the effectiveness of presenting highly novel stimulation in drug abuse prevention interventions aimed at at-risk high novelty/sensation seeking humans. The long-term objective of this work is to design a biologically-relevant prevention intervention strategy that can be evaluated in a controlled human laboratory and community-based project within the Center.